Previous studies have demonstrated that fibrinogen is an important determinant of metastatic potential, possibly by influencing tumor cell clearance by natural killer cells. However, the precise mechanism(s) by which the platelet/fibrinogen axis influences malignancy remain poorly understood. The experiments detailed in the proposal will use gene-targeting technology and in vivo murine tumor models to define the role of platelet activation, fibrin(ogen) and platelet/fibrin interactions in metastasis and natural killer cell mediated tumor surveillance. Additionally, the mechanistic significance of Mac-1 mediated fibrin(ogen)/NK cell interactions in NK cell mediated tumor clearance will be explored. The proposed experiments will test the following hypotheses: 1) platelet activation, fibrin polymer formation and platelet-fibrin(ogen) interactions are key determinants of the platelet/fibrinogen axis that determine metastatic potential, 2) tumor cell associated fibrin(ogen)-platelet microthrombi are an important factor in the trafficking and/or activation of cells related to innate tumor immunity (i.e. natural killer cells), and 3) fibrin(ogen) engagement of the beta2- integrin, Mac-l, is a mechanistic determinant of tumor call clearance by innate immunity. The proposal will provide an excellent opportunity for the applicant to expand his skills in molecular genetics, immunology tumor biology and pathology. The applicant will have the benefit of close mentorship by the sponsor, Jay Degen, Ph.D., a recognized leader in the field of molecular hemostasis and gene-targeting. The Cincinnati Children's Hospital Research Foundation will be an excellent setting for completing this proposal, providing the applicant with access to state-of-the-art resources and expertise. Together with an advisory committee consisting of experts in molecular immunology, tumor biology, hematopoiesis and signaling, the applicant will have the benefit of an ideal training environment. The planned program will provide the record of productivity, knowledge and skills necessary to establish a successful career as an independent physician/scientist.